title: Foldameric α/β-peptide analogs of the β-sheet-forming antiangiogenic anginex: structure and bioactivity.
abstract: The principles of β-sheet folding and design for α-peptidic sequences are well established, while those for sheet mimetics containing homologated amino acid building blocks are still under investigation. To reveal the structure-function relations of β-amino-acid-containing foldamers, we followed a top-down approach to study a series of α/β-peptidic analogs of anginex, a β-sheet-forming antiangiogenic peptide. Eight anginex analogs were developed by systematic α → β(3) substitutions and analyzed by using NMR and CD spectroscopy. The foldamers retained the β-sheet tendency, though with a decreased folding propensity. β-Sheet formation could be induced by a micellar environment, similarly to that of the parent peptide. The destructuring effect was higher when the α → β(3) exchange was located in the β-sheet core. Analysis of the β-sheet stability versus substitution pattern and the local conformational bias of the bulky β(3)V and β(3)I residues revealed that a mismatch between the H-bonding preferences of the α- and β-residues played a minor role in the structure-breaking effect. Temperature-dependent CD and NMR measurements showed that the hydrophobic stabilization was scaled-down for the α/β-peptides. Analysis of the biological activity of the foldamer peptides showed that four anginex derivatives dose-dependently inhibited the proliferation of a mouse endothelial cell line. The α → β(3) substitution strategy applied in this work can be a useful approach to the construction of bioactive β-sheet mimetics with a reduced aggregation tendency and improved pharmacokinetic properties.
authors.affiliation: SZTE-MTA Lendulet Foldamer Research Group, Institute of Pharmaceutical Chemistry, University of Szeged , Eötvös u. 6, H-6720 Szeged, Hungary.
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Hegedüs
authors.forename: Edit
authors.initials: E
authors.lastname: Wéber
authors.forename: Éva
authors.initials: É
authors.lastname: Kriston-Pál
authors.forename: Ildikó
authors.initials: I
authors.lastname: Makra
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Czibula
authors.forename: Éva
authors.initials: É
authors.lastname: Monostori
authors.forename: Tamás A
authors.initials: TA
authors.lastname: Martinek
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D010455:Peptides; C558923:anginex peptide